This invention relates to the administration of bacillus Calmette-Guerin in the treatment of superficial bladder tumors and, more particularly, to an improved kit and method for such administration through the use of an optimal diluent formulation.
Based upon the original work by Morales and associates, bacillus Calmette-Guerin (BCG) has been administered intravesically in the treatment and prophylaxis of recurrent bladder tumor. Morales et al., J. Urol., 116:180, 1976. In the initial study, 120 mg. BCG were reconstituted in 50 cc. normal saline and instilled via a catheter into the bladder. Patients were advised to retain the BCG solution for not less that 2 hours and additionally, patients received 5 mg. BCG intradermally. Treatments were given weekly for 6 weeks. This original regimen was arrived at arbitrarily and was amenable to modification as future data became available.
In subsequent studies, modification of this regimen focused on the elimination of the intradermal dose of BCG, increasing the number of weekly BCG treatments, introduction of maintenance BCG dosage schedules and introduction of other substrains of BCG. See Martinez-Pineiro, Bladder Tumors and Other Topics in Urological Oncology, Edited by M. Pavone-Macaluso et al., New York:Plenum Press, p. 175,1980; Brosman J. Urol., 36, 1985; Hudson et al., J. Urol., 138:295, 1987; Lamm et al., J. Urol., 135:272,1986; Brosman, J. Urol., 128:27, 1982; Lamm et al., J. Urol., 128:931, 1982; Lamm, J. Urol., 134:40, 1985; Mori et al. Urol. Int., 41:254,1986; and Kelley et al., J. Urol., 134:48, 1985. In these studies, little attention has been paid to the actual administration conditions of the individual doses of BCG. Diluents reported in the literature for the reconstitution of lyophilized BCG preparations include normal saline, phosphate buffered saline or sterile water. The retention time for each BCG dose in these prior studies has been 30 minutes to 2 hours.
Recent studies have suggested that an initial requisite step in mediating the antitumor effect of BCG is attachment of BCG organisms to matrix fibronectin at sites of urothelial disruption. Ratliff et al., J. Urol., 139:3:410, 1988. Fibronectin is a glycoprotein with a molecular weight of 440 kD. It is found in a soluble form in plasma and other body fluids, and in an insoluble (matrix) form on cell surfaces, basement membranes and extracellular matrixes. Mosher, Prog. Hemat. Thromb., 5:111,1980. It has been demonstrated that pretreatment of BCG with soluble fibronectin prevents the binding of BCG to matrix fibronectin exposed on the murine bladder wall after mucosal disruption. Ratliff et al., supra. The inhibition of intravesical BCG attachment resulted in the loss of antitumor activity. Ratliff et al., Cancer Res. 47:1762, 1987.
There has been a continuing need to determine the optimal composition and physical conditions for the diluent in which the BCG is suspended and the interval that BCG is exposed to fibronectin so as to maximize the efficacy of BCG administration.